The completion of the Trial to Reduce Insulin Dependent Diabetes in the Genetically at Risk ('TRIGR') will determine whether weaning to a formula in which (foreign) proteins have been extensively hydrolyzed, reduces disease risk for type 1 diabetes (T1D) in genetically susceptible children, as it does in rodent models. The Specific Aims are: I-a: To determine whether weaning to casein hydrolysate reduces the frequency of clinical diabetes; and I-b: To assess a potential shift in the age-adjusted incidence (not the cumulative incidence) of autoantibodies and T1D to a later time period in the group treated with the hydrolyzed study formula. This longest and largest, double-blind, randomized controlled trial in subjects with an affected first-degree relative and risk-associated HLA genotypes is currently in its 14th year. An international, multicenter consortium has been developed comprising 77 centers in 15 countries. Enrollment of 2159 eligible infants was completed successfully, providing a cushion above the required 2032 infants. The 6-8 month intervention designed to compare the effects of either hydrolyzed casein or standard cow milk based weaning formula was completed in 2007. Duration of breast-feeding was at the mothers' discretion and similar to or above background populations. All subjects are followed during and after the intervention period for at least 10 years with measurements of immune markers of intact cow milk exposure, diabetes predictive autoantibodies and the clinical and/or metabolic indices of diabetes (the end point at age 10-14 years). Currently all planning parameters have been met and drop- out rate is 2% with compliance at expected level. A large, cross-linked repository of stored sera, DNA, T-cell data, and cryopreserved peripheral blood mononuclear cells allows independently funded ancillary and mechanistic studies related to the natural history of prediabetes and the hypothesis to be tested. This application covers years 16- 18 for the International Coordinating Center and the Core Autoantibody Laboratory at the University of Helsinki and for the study centers in Europe and Australia which is submitted in tandem with those of the US coordinating center and clinical centers and that of the Data Management Unit. Funding is requested for completing the trial and reporting the outcome.